ba-1982-0199.ch032

32 Implantable Micropump for Insulin Delivery

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Effect of a Rate-Controlling Membrane M I C H A E L V. SEFTON University of Toronto, Department of Chemical Engineering and Applied Chemistry, Toronto, Ontario M5S 1A4, Canada

Using a controlled-release micropump with a 1.2-µm cellulose acetate membrane inserted between the insulin reservoir and the micropump solenoid, and a concentration-difference driving force (100 U/mL), the basal insulin delivery rate was 0.3 U/day and the degree of augmentation was 83

× at maximum

power input. This delivery rate remained constant during the 8-h experiment, in contrast with the performance of Nucleopore

1-µm

membranes upon which occlusive precipitates

quickly formed to lower the basal rate. The suggested inherent reliability of the device, the small reservoir, and the apparent absence of a problem with insulin precipitation may prove to be significant

advantages of the controlled-release micro-

pump. With this device, diabetologists will be able to assess the potential benefits to be derived from open-loop insulin delivery systems.

A

n estimated five million people in North America and 30 million in the world are diabetic. Almost half of these people require repeated, often

daily, injections of insulin to maintain approximately normal glucose levels. While gross metabolic control is achieved, diabetics are still subject to un-

avoidable complications. Conventional insulin therapy is inadequate for the restoration of normoglycemia sufficient to prevent these degenerative sequelae of diabetes (i). Hence, artificial pancreata have been designed and developed to deliver insulin continuously in direct response to the physiological need to provide the finer control of glycemia necessary for homeostasis in insulin-dependent diabetes. 0065-2393/82/0199-0511$06.00/0 ©1982 American Chemical Society

Cooper et al.; Biomaterials: Interfacial Phenomena and Applications Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

512

BIOMATERIALS: INTERFACIAL PHENOMENA AND APPLICATIONS

T h e c o n n e c t i o n b e t w e e n g l y c e m i a a n d the degenerative vascular c o m plications of diabetes w h i c h , i n t u r n , cause p r e m a t u r e death, is based o n a l i m i t e d a m o u n t of i n d i r e c t e v i d e n c e (2). P r o o f of a direct causal relationship b e t w e e n n o r m o g l y c e m i a a n d the degenerative sequelae of diabetes must await the results of c l i n i c a l trials of the various artificial pancreata c u r r e n t l y u n d e r d e v e l o p m e n t a r o u n d the w o r l d .


The Artificial Pancreas W h e t h e r o p e n - l o o p or c l o s e d - l o o p c o n t r o l is envisaged, the artificial pancreas consists of an i n s u l i n d e l i v e r y m e c h a n i s m or p u m p attached to an appropriate r e s e r v o i r a n d to a p o w e r supply/control package ( F i g u r e 1). T h e inadequacies of c u r r e n t glucose sensors (3,4) make o p e n - l o o p c o n t r o l the only practical o p e r a t i n g m o d e envisaged at this t i m e for the l o n g - t e r m treatment of a large n u m b e r of i n s u l i n - d e p e n d e n t diabetics. O p e n - l o o p c o n t r o l systems are characterized by operation at two levels: basal d e l i v e r y u p to a n d f o l l o w i n g the absorption of meals, and a u g m e n t e d d e l i v e r y for short p e r i o d s associated w i t h the absorption of meals adjusted to the i n s u l i n r e q u i r e m e n t of the respective m e a l . A u g m e n t e d flow rates have ranged f r o m 4 x basal (5) to 15 X basal (6, 7), and a u g m e n t e d periods have varied f r o m a single bolus injection/meal i n humans (8) to 7 h/day i n dogs (9).

Figure 1. Artificial pancreas block diagram. Closed-loop control (—) uses the sensor ana programmers to directflowcontroller. In open-loop control (—), augmentation is initiated by the diabetic, without the sensor. Typical design criteria are indicated on the right-hand side of the drawing.


32.

SEFTON

Implantable Micropump for Insulin Delivery

513

T h e characteristics a n d l i m i t a t i o n s o f these devices recently w e r e r e v i e w e d (4), and w e r e the subject of a recent s y m p o s i u m (10). Subsequent to this r e v i e w , o t h e r researchers have r e p o r t e d t h e i r success u s i n g o p e n - l o o p i n s u l i n d e l i v e r y systems to m a i n t a i n n o r m o g l y c e m i a i n dogs ( 7 , 9 ) and i n humans (8,11-14). T h e effects o f this restoration of n o r m o g l y c e m i a o n d i abetic m e t a b o l i s m a n d b l o o d c h e m i s t r y are b e g i n n i n g to be r e p o r t e d (15-19), but no clear e v i d e n c e of l o n g - t e r m beneficial effects of n o r m o g l y c e m i a have


yet b e e n o b t a i n e d .

Insulin Pumps U n l i k e the b e d s i d e or portable i n s u l i n d e l i v e r y systems for w h i c h c o m m e r c i a l l y available peristaltic or syringe p u m p s may b e u s e d , the key c o m p o n e n t of an i m p l a n t a b l e (open-loop) artificial pancreas is the specially d e v e l oped miniature insulin p u m p . A l t h o u g h n u m e r o u s devices have b e e n d e v e l o p e d (20) for the c o n t r o l l e d d e l i v e r y of pharmaceuticals, o n l y three have b e e n used for i n s u l i n d e l i v e r y and can b e c h a r a c t e r i z e d as i m p l a n t a b l e (7,11,21 ). O t h e r devices for i n s u l i n d e l i v e r y are o r have b e e n u n d e r d e v e l o p m e n t , but little is k n o w n of t h e i r performance characteristics (22,23). T h e p r i m a r y l i m i t a t i o n c u r r e n t l y facing t h e d e v e l o p m e n t and use o f these i m p l a n t a b l e m i c r o p u m p s is the p r e c i p i t a t i o n of i n s u l i n on the p u m p components (7,11,14,31),

a l t h o u g h bicarbonate (33), certain s e r u m c o m -

ponents (25), or a m i n o acides (32) may m i n i m i z e or prevent i n s u l i n aggregation. T h e s e precipitates, i f they accumulate, t e n d to occlude the flow channels i n t h e p u m p a n d p a r t i c u l a r l y t h e fine bore t u b i n g o r valves that are integral parts of these devices. A d d i t i o n a l c o n c e r n is related to the r e l i a b i l i t y and i n h e r e n t safety of these devices a n d to t h e i r ability to use small, concentrated i n s u l i n reservoirs.

Controlled-Release Micropump T h e « controlled-release m i c r o p u m p ( F i g u r e 2) is a recently i n v e n t e d device that uses the p r i n c i p l e s of m e m b r a n e transport and c o n t r o l l e d release of drugs to d e l i v e r i n s u l i n at variable rates (20,26). W i t h a suitable s u p p l y o f i n s u l i n c o n n e c t e d to the p u m p , the concentration and/or pressure difference across the m e m b r a n e results i n diffusion or b u l k transport t h r o u g h the m e m brane^). T h i s process is the basal d e l i v e r y and requires no external p o w e r source. A u g m e n t e d d e l i v e r y is achieved b y repeated compression of the foam m e m b r a n e b y t h e coated m i l d - s t e e l p i s t o n . T h e piston is the core o f the solenoid, and c o m p r e s s i o n is effected w h e n c u r r e n t is a p p l i e d to the solenoid coil. I n t e r r u p t i o n of the c u r r e n t causes the m e m b r a n e to relax, d r a w i n g m o r e d r u g into the m e m b r a n e i n p r e p a r a t i o n for the next compression cycle. E n e r g y c o n s u m p t i o n is l o w since p o w e r is c o n s u m e d o n l y d u r i n g the postprandial d e l i v e r y phase, a n d even t h e n o n l y d u r i n g t h e compression Cooper et al.; Biomaterials: Interfacial Phenomena and Applications Advances in Chemistry; American Chemical Society: Washington, DC, 1982.

514


RATE CONTROLLING MEMBRANE —


POWER SUPPLY SOLENOID CORE/PISTON

PUMP BARREL

SOLENOID

LUCITE ROD FOAM "MEMBRANE" POROUS SUPPORT

Industrial and Engineering Chemistry Product Research and Development

Figure 2. Schematic of the controlled-release micropump. Rate-controlling membrane is not present in early prototypes (26).

p o r t i o n of the cycle (power for t y p i c a l therapeutic use: 60 W peak X 5 ms " o n " t i m e = 0.3 J/compression stroke, w i t h a f r e q u e n c y of 30 strokes/min). T h i s chapter reports o n t h e c o n t i n u e d d e v e l o p m e n t of this p u m p w i t h particular emphasis o n t h e use o f a r a t e - c o n t r o l l i n g m e m b r a n e to lower the basal rate and raise the d e g r e e of a u g m e n t a t i o n to c l i n i c a l l y acceptable levels.

Experimental Micropump Fabrication. Lucite prototypes were prepared as described earlier (26). Glass prototypes with 2000 turns of 36-gauge wire (R = 80 Ω) were prepared as described before (20) except that the sintered glass disk was glued to the end of the 11.3-cm long glass tube (7-mm o.d.), and a 7-cm length of tapered tubing (a portion of pasteur pipette) was glued to the disk and used as the pump outlet. The lucite spacer was 5 mm long, making the nominal magnetic field gap 1.7 cm. The power supply (26) provided an interrupted dc current for the solenoid with an "on" time of of 5 ms at a frequency of 30 strokes/min for these experiments. Membranes. A 1-cm thick, approximately 5-mm-diameter disk of HYPOL nonwicking hydrophilic polyurethane foam was used in all experiments. Only disks


32.

SEFTON

515


with an air permeability of 5 ± 1 X 10" cm at an air flow rate of 850 cm /min were used. No specific conditioning of the foam was done nor was any attempt made to remove extractables from the cured foam. To improve the delivery, 13-mm-diameter rate-controlling membranes held in a Swinnex filter chamber (Millipore Corp.) were inserted in the delivery line between the insulin reservoir and the micropump. The effective membrane area was 0.7 cm . Membranes investigated were l-μπι and 8-μπι pore size polycarbonate filters (Nuclepore Corp.), 0.45-μιη cellulosic microporous filters (Amicon Corp.), Cuprophane PT-150 (from Ultra-Flow 145 Dialyser, Travenol Laboratories), and 0.2-μΐΏ and 1.2-μπι pore size cellulose acetate filters (Schleicher and Schuell O E 66 and ST 69). Pressure-Difference Driving Force. The falling head permeameter (26) was used to measure the volumetric flow rate through the controlled-release micropump with a pressure difference driving force. The pressure difference in this permeameter is the difference in height of insulin solution in an open vertical graduated pipette or tube, acting as the upstream reservoir, and the constant height of liquid in a down stream reservoir in which the pump outlet is immersed. The rate of decrease of insulin solution in the upstream reservoir was measured and converted to overall flow resistance, or basal and augmented flow rates as required. Different pipettes or tubes were used to cover a range offlowrates: 2-mL pipette (3.36-mm i.d.), 0.5-mL pipette (1.96-mm i.d.), or a length of PE20 Intramedic tubing (0.38-mm i.d., Clay Adams). The resistances of the permeameter itself and the filter chamber were estimated by measuring the flow resistance without a membrane and without the controlledrelease micropump. Unfortunately, the resistance of the PE20 tubing, unlike the others, was very dependent on the height in the permeameter (i.e., length of tubing), complicating the correction for the resistance. The feed reservoir consisted of 0.4 U/mL mixed bovine/porcine insulin (Toronto Insulin, Connaught Laboratores Ltd.) in 0.05M phosphate-buffered saline (pH 7.4) containing 1% formaldehyde. Concentration-Difference Driving Force. A shorter glass prototype in which the membrane held in the Swinnex chamber was attached directly to the pump barrel was used for these experiments. The pump barrel (7-mm o.d. glass tube) was 4 cm long with the membrane held approximately 5 cm from the sintered glass disk. The tapered glass tube was replaced with the male end (1 cm long) of a 1-mL syringe (Plastipak, B-D). All other components were the same as the previously described glass prototype. The pump including filter chamber weighed 40 g. 7

2

3


2

Insulin delivery rate was determined by following the increase in I-insulin concentration in a 2-mL downstream reservoir. The reservoir was connected via a siphon to a test tube that fit into the sampling well of a Nal scintillation detector. A 1-mL sample of the downstream solution was taken by appropriate manipulation of the siphon arm heights. The detector was connected to an Eberline MS-2 Scaler (Datamex Ltd.). The insulin reservoir solution contained 100 U/mL Toronto insulin and approximately 0.5 μα/mL of I-insulin (Amersham-Searle). Care had to be taken to fill the micropump with liquid since the presence of air bubbles in any of the lines would reduce the delivery rate. The portion of the pump below the membrane was filled with insulin-free phosphate buffered saline containing 0.5% (w/v) m-cresol (a preservative) via a tube connected to the pump outlet. When this portion was full, the membrane was laid onto the membrane support portion of the chamber, and the upper half of the chamber was reconnected to the controlledrelease micropump. The upper half of the chamber constituted the 1-cm upstream reservoir for these experiments and was filled with radioactive feed solution through a needle inserted horizontally into the side of the membrane chamber. The top of the chamber was connected to a plastic three-way valve using the appropriate Luer-lok connections to permit filling. The valve was turned to seal the chamber and eliminate the pressure difference before the experiment. One of the ports of the valve was used 125

125

3


516


to collect a sample of feed solution to measure its concentration and to avoid the problem of correcting for adsorption. Neither upstream nor downstream reservoirs were stirred. Care was taken to avoid dilution of the upstream solution with insulinfree saline.

Results T h e effects o f o p e r a t i n g parameters (voltage, f r e q u e n c y of c o m p r e s s i o n , and pressure difference) a n d some design parameters w e r e demonstrated i n Downloaded by UNIV OF CALIFORNIA SAN DIEGO on April 1, 2016 | http://pubs.acs.org Publication Date: July 27, 1982 | doi: 10.1021/ba-1982-0199.ch032

earlier p u b l i c a t i o n s (20,26). T h e results p r e s e n t e d here focus o n t h e ef fect o f a r a t e - c o n t r o l l i n g m e m b r a n e b e t w e e n the solenoid a n d t h e i n s u l i n reservoir. Pressure-Difference D r i v i n g Force.

T h e effect o f a 1-μπι polycar

bonate m i c r o p o r o u s filter o n basal a n d a u g m e n t e d d e l i v e r y i n the c o n t r o l l e d release m i c r o p u m p d u e to a pressure difference is shown i n F i g u r e 3 . A s the pressure difference was l o w e r e d (i.e., as t h e l i q u i d level d r o p p e d i n the falling head p e r m e a m e t e r ) t h e basal flow rate was r e d u c e d to less than 0.2 mL/day (pressure difference, a p p r o x i m a t e l y 0.8 c m H 0 ) . A t this basal rate, 2

operation w i t h a 1 0 0 - U / m L reservoir becomes practical. M o r e i m p o r t a n t l y , the degree o f a u g m e n t a t i o n was increased to more than 10 X f r o m the 20 î

I

10

4

1

1 1

1

1 1 , 1IJ

1

1

1 1

1

1

1 1 1—I—I

10"

ΙΟ

3

2

BASAL FLOW RATE, Q (mL/min) 0


Figure 3. Degree of augmentation with a l-^m polycarbonate filter as the rate-controlling membrane as a function of initial basalflow.(26). Basalflowwas varied by lowering the pressure difference from 3000 dyn/cm to 800 dyn/cm in the falling head permeameter. The PE20 tubing used in the permeameter to give an overall initial basal pump resistance varying from 1 x 10 to 7.6 x 10 dyn mini cm . Augmentations were measured at a time-averaged power input of250 mW (90 v, so Ω ; . 2

2

6

5


6

32.

517


SEFTON

1.5-2 X that was o b t a i n e d w i t h o u t this m e m b r a n e . U n d e r these conditions the controlled-release m i c r o p u m p meets the m i n i m u m design c r i t e r i a for an i n s u l i n d e l i v e r y system. Since these data w e r e o b t a i n e d w i t h the

PE20

t u b i n g i n the p e r m e a m e t e r , a n d the P E 2 0 t u b i n g offered an a d d i t i o n a l sig nificant resistance to flow (ranging f r o m 7 Χ 1 0 - 3 Χ 10 dynes min/cm ), the 5

6

5

basal flow rates w e r e l o w e r , at any pressure difference, than w o u l d have b e e n obtained w i t h o u t the p e r m e a m e t e r . O t h e r m e m b r a n e s similarly l o w e r e d the


basal rate i n accordance w i t h t h e i r resistance relative to that of the rest of the p u m p a n d the p e r m e a m e t e r . T h e resistance of the m e m b r a n e was deter m i n e d b y difference b e t w e e n the total resistance a n d the resistance w i t h o u t a m e m b r a n e for the various p e r m e a m e t e r s . W h i l e the 1-μπι polycarbonate m e m b r a n e p r o v i d e d the appropriate resistance to give the d e s i r e d basal rate, this resistance was v e r y t i m e de p e n d e n t (Table I). U n l i k e the 8-μπι polycarbonate or 0.45-μπι cellulosic m e m b r a n e , the flow resistance t h r o u g h the 1-μπι m e m b r a n e increased six fold over a 5-h p e r i o d . T h i s was a t t r i b u t e d to the formation of an i n s u l i n precipitate o n the m e m b r a n e w h i c h b l o c k e d the pores of the m e m b r a n e . F i g u r e 4 shows these precipitates for a m e m b r a n e that h a d b e e n p l a c e d between the H y p o l foam a n d the porous disk i n an earlier prototype (26). P r e s u m a b l y , the larger pores i n the 8-μπι polycarbonate m e m b r a n e w e r e not significantly affected b y the precipitates, a n d fewer precipitates h a d f o r m e d on the m o r e h y d r o p h i l i c 0 . 4 5 - μ π ι m e m b r a n e d u r i n g the t i m e of the e x p e r i ments. I n other e x p e r i m e n t s (27) the p e r m e a b i l i t y of C u p r o p h a n e a n d other h y d r o p h i l i c m e m b r a n e s was m e a s u r e d over a 7-day p e r i o d w i t h o u t any no ticeable decrease i n rate. T h e apparent difference i n behavior of h y d r o p h i l i c and h y d r o p h o b i c m e m b r a n e s is not c u r r e n t l y k n o w n , although this differ ence p r o b a b l y reflects differences i n the adsorption pattern of i n s u l i n on the different m e m b r a n e s (34). T a b l e I. E f f e c t o f M e m b r a n e o n B a s a l F l o w r a t e D e c a y

Membrane 8-μπι Polycarbonate (Nuclepore) l - μ π ι Polycarbonate (Nuclepore) 0.45-μπι C e l l u l o s i c (Amicon) c

R

Time (h)

a

m

0

1

1

1.01

1.03

1

1.4

2

2.7

5.9

1

1.01

1.025

1.045

1.084

630 3.4 x 10 2.6 x 1 0

3

s

2

3 —

—

Note: Data determined by interpolation. R = membrane resistance at time t; R° = initial membrane resistance (dyn min/cm ). R ° = total resistance — resistance without membrane R° determined from 2-mL pipette, all others using 0.5-mL pipette. o

a

t

m

m

b

C


5


518



Figure 4. Scanning electron micrograph of precipitates on l-^m polycarbonate filter after 2 h of use. This membrane was placed between the foam membrane and the porous support (26). C o n c e n t r a t i o n - D i f f e r e n c e D r i v i n g F o r c e . T h e realization that h i g h augmentations w e r e best o b t a i n e d at l o w pressure differences l e d to the design of a p r o t o t y p e that u s e d a concentration-difference d r i v i n g force. T h e basal a n d a u g m e n t e d flows t h r o u g h this device are shown i n F i g u r e 5 for various h y d r o p h i l i c m e m b r a n e s . F r o m t h e 1 0 0 - U / m L reservoir, basal rates ranged f r o m less than 0.3 to 1.1 U/day, w h i l e degrees of augmentation for the 1.2-μιτι c e l l u l o s e acetate m e m b r a n e w e r e as h i g h as 83 x the basal rate at 100 V (time-averaged p o w e r = 3 1 0 m W ) . Because o f the less-than-detectable basal rate for t h e o t h e r m e m b r a n e s , these augmentations were also very h i g h , a l t h o u g h t h e a u g m e n t e d flow rates w e r e lower than for the 1.2-μπι cellulose acetate m e m b r a n e . T h e significant diffusion resistance o f the controlled-release m i c r o p u m p itself is also apparent f r o m F i g u r e 5. C o m p a r i n g basal rates, t h e p u m p b a r r e l , outlet, a n d m e m b r a n e c h a m b e r offer a p p r o x i m a t e l y 2 7 % of the total resistance of the m i c r o p u m p w i t h the 1.2-μπι


32.

SEFTON


cellulose acetate m e m b r a n e .

519

D u r i n g t h e 8 - h m a x i m u m d u r a t i o n o f these

experiments, no noticeable decrease i n i n s u l i n d e l i v e r y rate was noted, that is, after a short i n i t i a l unsteady-state p e r i o d , t h e rate of increase of i n s u l i n concentration i n t h e d o w n s t r e a m reservoir was constant. T h e duration o f these unsteady-state

p e r i o d s is o b v i o u s l y i m p o r t a n t to t h e design o f t h e

a u g m e n t e d d e l i v e r y p r o g r a m s . To m i n i m i z e these t i m e lags, the current prototype has b e e n s h o r t e n e d f u r t h e r to give a device w i t h a total diffusion


path of a p p r o x i m a t e l y 2 c m .

Discussion A l t h o u g h t h e i n i t i a l prototypes w e r e d e s i g n e d for use w i t h an i n s u l i n reservoir s u p p l y i n g d r u g to t h e p u m p inlet at constant pressure (20,26), these m o r e recent e x p e r i m e n t s indicate that t h e device performs better (higher augmentation/power ratio) a n d at t h e r e q u i r e d i n s u l i n basal rate ( — 20 U/day) w i t h a constant-concentration

upstream reservoir. F u r t h e r -

Voltage (V) Figure 5. Basal and augmented insulin delivery rates with various membranes as rate-controlling membranes, using a concentration-difference (100 U/mL) driving force. Peak voltage used as abscissa (R = 80 Ω, 30 strokes/min, 5 ms 'on time"); voltage = 0 corresponds to basal rate. Key: ·, no membrane; A, 1.2-^m cellulose acetate; •, 0.2-μm cellulose acetate; and •, Cuprophane.


520


m o r e , the maintenance of a constant-pressure difference, p a r t i c u l a r l y at these l o w levels, i n v i v o is not a s i m p l e matter. T h e constant-concentration reservoir, o n the other h a n d , w o u l d s i m p l y be a c h a m b e r containing i n s u l i n at u n i t activity (solid i n s u l i n d i s p e r s e d i n a nontoxic m e d i u m ) separated from the p u m p itself b y the h y d r o p h i l i c rate-controlling m e m b r a n e . T h e s e reservoirs w o u l d contain 1 0 , 0 0 0 - 2 0 , 0 0 0 U / c m ; consequently, at a c o n s u m p t i o n rate of 50 U/day, a 2 - c m reservoir c o u l d contain e n o u g h i n s u l i n for 1-2 years w i t h o u t a r e f i l l . T h e r e f o r e , the total mass of the device (without p o w e r pack) c o u l d be kept to less than 50 g a n d yet be useful for m o r e than 1 year. A similar s o l i d i n s u l i n reservoir has b e e n used for constant rate-controlled release of i n s u l i n (28), a n d the i n s u l i n activity has b e e n retained for more than 8 months at 37°C i n this f o r m (29). 3


3

A u g m e n t e d d e l i v e r y is achieved w i t h o u t valves i n the controlled-release m i c r o p u m p , a n d h e n c e the m e c h a n i c a l u n r e l i a b i l i t y associated w i t h the i n a d vertent o p e n i n g a n d s t i c k i n g o f valves, w i t h c o m p l e x motors, o r w i t h the peristaltic action of a rotating metal c o m p o n e n t on a soft plastic tube is avoided. F u r t h e r m o r e , i n the controlled-release m i c r o p u m p , basal d e l i v e r y is not achieved b y r e g u l a t i n g a large f l o w rate as it is done i n valve-operated systems. T h e r e l i a b i l i t y associated w i t h the repeated compression of the foam is, however, of great c o n c e r n . Results a c q u i r e d to date indicate that for a p u m p fabricated w i t h o n l y l i m i t e d care, a life of 1100 h (for continuous a u g m e n t e d delivery) can be expected (30); this result corresponds to a life of 1 year of n o r m a l use. I n s u l i n d e p o s i t i o n i n the controlled-release m i c r o p u m p is not expected to be i m p o r t a n t . W h i l e it was significant i n one of the prototypes ( F i g u r e 4), c h a n g i n g the r a t e - c o n t r o l l i n g m e m b r a n e f r o m a h y d r o p h o b i c polycarbonate filter to a h y d r o p h i l i c C u p r o p h a n e or cellulose acetate m e m b r a n e has apparently e l i m i n a t e d the p r o b l e m . A l t h o u g h the situation may be different as l o n g e r - t e r m e x p e r i m e n t s are p e r f o r m e d , p r e s u m a b l y the p r o b l e m s that may arise may relate m o r e to the b i o l o g i c a l stability of the i n s u l i n reservoir than to i n s u l i n d e p o s i t i o n . T h e m e c h a n i s m of action of the controlled-release m i c r o p u m p is u n clear. W i t h a pressure difference, the r a p i d oscillatory m o v e m e n t of the piston d u r i n g a u g m e n t e d d e l i v e r y may be responsible for the increased d e l i v e r y rate b y l o w e r i n g the overall resistance of the m i c r o p u m p to b u l k flow (35). W h e n o n l y a c o n c e n t r a t i o n difference exists, o n the other h a n d , augmentation can be a t t r i b u t e d to a pressure difference s u p e r i m p o s e d d u r i n g piston m o v e m e n t on the basal concentration difference, or to a m i x i n g effect associated w i t h p i s t o n m o v e m e n t . T h e p h y s i c a l relationship b e t w e e n piston m o v e m e n t a n d a u g m e n t a t i o n remains to be d e f i n e d . A n u m b e r of concerns r e g a r d i n g o p e n - l o o p d e l i v e r y of i n s u l i n i n general, and d e l i v e r y of i n s u l i n b y the controlled-release m i c r o p u m p , i n p a r t i c u lar, r e m a i n to be r e s o l v e d . T h e o p t i m u m site of i n s u l i n d e l i v e r y (intravenous


32.

SEFTON


521

or subcutaneous), the tissue reaction to the pump outlet, the optimum method of adjusting the basal rate for patient-to-patient

variability, pump

reliability, and the time lags between steady-state basal and augmented delivery rates must be determined or assessed. Furthermore, whether the restoration of nomoglycemia leads to reduction of or prevention of the degenerative complications of diabetes must be determined. In addition, proof that open-loop control of glycemia results in a better degree of control than


multiple injection therapy or, alternatively, that there is a subgroup of diabetics for whom open-loop insulin delivery would be the preferred mode of treatment remains to be shown. These questions must be addressed before open-loop delivery of insulin with the controlled-release micropump becomes a clinically acceptable mode of therapy.

Conclusions The controlled-release micropump is a simple means of delivering insulin at variable rates to control the glucose level of insulin-dependent diabetics at physiological levels. Operating with a concentration-difference driving force, the controlled-release micropump delivers insulin at a low constant rate which can be augmented more than 80 X in one prototype by repeated compression of a foam membrane. The suggested inherent reliability of the device, the small reservoir, and the apparent absence of a problem with insulin precipitation may prove to be significant advantages of the controlledreleased micropump compared to other proposed insulin delivery systems. With this device, diabetologists and biomedical researchers will be able to examine the relationship between safe and reliable metabolic control and the incidence of degenerative complications, and to assess the potential benefits to be derived from open-loop insulin delivery systems.

Acknowledgments The support of the J. P. Bickell Foundation and the technical assistance of K. J. Burns, P. J. Cahill, and R. Sirisko are gratefully acknowledged.

Literature Cited 1. 2. 3. 4.

Cahill, G. F.; Etzwiler, D. D.; Freinkel, N. Diabetes 1976, 25, 237-239. Tchobroutsky, G., Diabetologia 1978, 15, 143-152. Albisser, A. M . ; Leibel, B. S. Clinics in Endocrin and Metab. 1977, 6(2), 457. Santiago, J. V . ; Clemens, A. H.; Clarke, W. L . ; Kipnis, D. M . Diabetes 1979, 28, 71-84. 5. Hepp, K. D . ; Renner, R.; von Funcke, H . J.; Mehnert, H.; Haerten, R.; Kresse, H. Horm. Metab. Res. Suppl. 1977, 7, 72-76. 6. Slama, G . ; Hautecouverture, M . ; Assan, R.; Tchobroutsky, G. Diabetes 1974, 23, 732. 7. Blackshear, P. J.; Rohde, T. D.; Grotteng, J. C.; Dorman, F. D.; Perkins, P. R.; Varco, R. L . ; Buchwald, H . Diabetes 1979, 28, 634-639.



522


8. Tamborlane, W. V . ; Sherwin, R. S.; Genel, M.; Felig, P. N. Engl. J. Med. 1979, 300(11), 573-578. 9. Goriya, Y.; Bahoric, Α.; Marliss, Ε. B.; Zimman, B.; Albisser, A.M.;Diabetes 1979, 28, 558-564. 10. "Feedback-controlled and preprogrammed insulin infusion in diabetes mellitus." Workshop Schloss Reisenberg. Horm. Metab. Res. Suppl. 1979, 8, 1-211. 11. Irsigler, K.; Kritz, H . Diabetes 1979, 28, 196-203. 12. Pickup, J. C . ; White, M . C . ; Keen, H.; Parsons, J. Α.; Alberti, K. G . M . M . Lancet, 1979, October 27, 870-873. 13. Kolendorf, K.; Bojesen, J.; Lorup, B. Diabetologia 1980, 18, 141-145. 14. Champion, M.; Shepherd, G . ; Rodger, N. W.; Dupre, J. Diabetes Astr. 1979, 28(156), 383. 15. Pickup, J. C.; Keen, H.; Parson, J. Α.; Alberti, K. G. M . M.; Rowe, A. S. Lancet 1979, June 16, 1255-1257. 16. Tamborlane, W. V . ; Sherwin, R. S.; Genel, M.; Felig, P. Lancet 1979, June 16, 1258-1261. 17. Bolli, G . ; Cartechinni, M . G . ; Compagnucci, P.; Santeusanio, F.; MassiBendeti, M.; Calabrese, G . ; Puxeddu, Α.; Brunetti, P. Diabetologia 1980, 18, 125-130. 18. Gertner, J. M.; Tamborlane, W. V.; Horst, R. L.; Sherwin, R. S.; Felig, P.; Genel, M . J. Clin. Endocrinol. Metab. 1980, 50, 862-866. 19. Hanna, A. K.; Zinman, B.; Nakhooda, A. F.; Minuk, H . L . ; Stokes, E . F.; Albisser, A. M.; Leibell, B. S.; Marliss, Ε. B. Metabolism 1980, 29(4), 321-332. 20. Sefton, M . V.; Lusher, H . M.; Firth, S. R.; Waher, M . U. Ann. Biomed. Eng. 1979, 7, 329-343. 21. Albisser, A. M.; Jackman, W. J.; Ferguson, R.; Bahoric, Α.; Goriya, Y. Med. Prog. Technol. 1978, 5, 187-193. 22. Thomas, L. J.; Bessman, S. P. Trans. Am. Soc. Artif. Intern. Organs 1975, 21, 516-520. 23. Nalecz, M.; Lewandowski, J.; Werynski, Α.; Zawicki, I. Artif. Organs 1978, 305-309. 24. Lougheed, W.; Albisser, A. M . Int. J. Artif. Organs 1980, 3, 50-56. 25. Albisser, A. M.; Lougheed, W.; Perlman, K.; Bahoric, A. Diabetes 1980, 29(3), 241-243. 26. Sefton, M . V.; Burns, K. J. Ind. Eng. Chem. Prod. Res. Dev. 1981, 20, 1-5. 27. Sefton, M . V.; Nishimura, E. J. Pharm. Sci. 1980, 69, 208-209. 28. Creque, H . M.; Langer, R.; Folkman, J. Diabetes 1980, 29, 37-40. 29. Langer, R. S., personal communication. 30. Burns, K. J. M.A.Sc. Thesis, University of Toronto, 1980. 31. Lougheed, W. D . , Woulfe-Flanagan, H.; Clement, J. R.; Albisser, A. M . Di abetologia 1980, 19, 1-9. 32. Bringer, J. Heldt, Α.; Grodsky, G. M . Diabetes 1981, 30, 83-85. 33. Lougheed, W. D . ; Fischer, U . ; Perlman, K.; Albisser, A. M . Diabetologia 1981, 20, 51-53. 34. Antonacci, G . ; Sefton, M . V. unpublished data. 35. Treen, M . E. B.A.Sc. Thesis, University of Toronto, 1979. ;

R E C E I V E D for review January 16, 1981. A C C E P T E D September 30, 1981.


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